Congestive Heart Failure
Congestive heart failure (CHF) is characterized by activation of neurohormonal systems such as the renin-angiotensin, sympathetic nervous system and vasopressin. It is commonly accepted that increased activity of these three vasoconstrictor systems plays a major role in the pathophysiology of CHF and may contribute to the clinical deterioration of patients with this syndrome. In particular, it has been documented that neurohormonal activation may have detrimental effects on the cardiovascular system and on the kidney. These include systemic vasoconstriction with increased afterload and the development of cardiac hypertrophy. In addition, neurohormonal activation may lead to deterioration in renal function, renal vasoconstriction, salt and water retention, and consequently edema formation (Dzau, 1987).
Cardiac hypertrophy is a major risk factor of cardiovascular mortality and morbidity (de Simone et al, 2001). It is a general adaptive response to states of hyperfunction (Meerson et al, 1996), and is observed in a wide variety of physiological and pathologic states, including pressure overload, volume overload, and excessive exposure to neurohumoral and metabolic stimuli. At its first stages, hypertrophy is a compensatory response. With the progression of the initial stimulus, a transition occurs in which an irreversible decompensation in cardiac function takes place, leading to heart failure, as well as to an increased tendency to develop arrhythmias (Chien, 1999; Swynghedauw and Baillard, 2000). The trigger for this transition from compensated hypertrophy to decompensation is unknown. Morphological and histological analyses reveal that decompensated hypertrophy and heart failure are usually characterized by ventricular dilation and collagen deposition, resulting in cardiac fibrosis and, subsequently, in myocardial stiffness.
Although of great importance, the mechanisms underlying the cardiac hypertrophy and fibrotic response remain poorly understood. It has been suggested that both the circulating and local myocardial neurohumoral systems such as renin-angiotensin-aldosterone system (RAAS) play a role in the development of ventricular hypertrophy and fibrosis (Dzau, 1987; Watkins et al, 1976). Similarly, activation of the sympathetic nervous system contributes to sodium retention, and to cardiac hypertrophy and fibrosis in clinical and experimental heart failure (Hostetter et al., 1983; Abassi et al. 1990; Brodsky et al., 1998).
Renal Failure
Acute renal failure (ARF) is a syndrome characterized by a sudden decrease in kidney function leading to a decrease or sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, conserve electrolytes and maintain fluid balance. It is a frequent clinical problem, particularly in the intensive care unit, where it is associated with a mortality of between 50% and 80% (Schrier et al, 2004). ARF may occur following exposure to various therapeutic agents such as cyclosporine, aminoglycosides, nonsteroidal antiinflammatory drugs, cisplatin, amphotericin B, or procedures, e.g., radiocontrast media, or exposure to heavy metal, which inflict toxic and ischemic damage to the renal tissue (Green et al, 2000).
The mechanisms underlying ARF involve both vascular and tubular factors (Kribben et al, 1999). An ischemic insult to the kidney due to hypoperfusion will, in general, be the cause of the ARF. While a decrease in renal blood flow with diminished oxygen and substrate delivery to the tubule cells is an important ischemic factor, it must be remembered that a relative increase in oxygen demand by the tubule is also a factor in renal ischemia. Renal ischemia leads to a series of cellular events which might culminate in organ failure, depending on the cell type and the duration of ischemia. It was assumed that reperfusion, instituted before irreversible damage to the tissue occurred, would limit the insult to the organ. Contrary to such expectations, it was reported that reperfusion enhances renal damage (Canavese et al., 1988). Several suggestions for the basis of this ‘reperfusion injury’ have been proposed. It has been linked to an attenuated restoration in renal blood flow which returns only to 60% of its preischemic value (Arendshorst et al., 1975; Cristol et al., 1993). Others have suggested that reactive oxygen species (ROS) generated during ischemia and reperfusion in the mitochondria, cause the damage (Canavese et al., 1988; Greene et al., 1991).
Chronic renal failure (CRF) is the progressive loss of kidney function. The kidneys attempt to compensate for renal damage by hyperfiltration (excessive straining of the blood) within the remaining functional nephrons (filtering units that consist of a glomerulus and corresponding tubule). Over time, hyperfiltration causes further loss of function.
Chronic loss of function causes generalized wasting (shrinking in size) and progressive scarring within all parts of the kidneys. In time, overall scarring obscures the site of the initial damage. Yet, it is not until over 70% of the normal combined function of both kidneys is lost that most patients begin to experience symptoms of kidney failure.
Propargylamine and Propargylamine Derivatives
Rasagiline, R(+)-N-propargyl-1-aminoindan, a highly potent selective irreversible monoamine oxidase (MAO)-B inhibitor, has been shown to exhibit neuroprotective activity and antiapoptotic effects against a variety of insults in cell cultures and in vivo.
Rasagiline is being developed for Parkinson's disease as monotherapy or as an adjunct to L-dopa therapy (Youdim et al., 2001; Parkinson Study Group, 2002; Finberg and Youdim, 2002; Gassen et al., 2003). Phase III controlled studies have shown that rasagiline is effective with a dose of as low as 1 mg/kg in monotherapy (Parkinson Study group, 2002) and as an adjunct to L-dopa, comparable in its effect to the anti-Parkinson catechol-O-methyltranferase (COMT) inhibitor, entacapone (Brooks and Sagar, 2003). Rasagiline has recently finished the phase III clinical trials and has been approved for Parkinson's disease.
Rasagiline exhibits neuroprotective activities both in vitro and in vivo (for review see Mandel et al., 2003; Youdim et al., 2003) which may contribute to its possible disease modifying activity. It is metabolized to its major two metabolites: aminoindan (TVP-136) and S(−)-N-propargyl-1-aminoindan (TVP-1022) (Youdim et al., 2001), which also have neuroprotective activity against serum deprivation and 1-methamphetamine-induced neurotoxicity in partially differentiated PC-12 cells (Am et al., 2004).
By contrast, selegiline (1-deprenyl), a selective MAO-B inhibitor which is a useful anti-Parkinson drug both in monotherapy (Parkinson Study Group, 1989) and as an adjunct to L-DOPA therapy, and has L-DOPA sparing action (Birkmayer et al., 1977; Riederer and Rihne, 1992; Parkinson Study Group, 1989), is a propargyl derivative of 1-methamphetamine. Thus, the major metabolite of selegiline, 1-methamphetamine (Szoko et al., 1999; Kraemer and Maurer, 2002; Shin, 1997), is neurotoxic (Abu-Raya et al., 2003; Am et al., 2004). In contrast to aminoindan, L-methamphetamine prevents the neuroprotective activities of rasagiline and selegiline in partially differentiated cultured PC-12 cells (Am et al., 2004).
Selegiline and methamphetamine, unlike rasagiline and aminoindan, have sympathomimetic activity (Simpson, 1978) that increases heart rate and blood pressure (Finberg et al., 1990; Finberg et al., 1999). Recent studies (Glezer and Finberg, 2003) have indicated that the sympathomimetic action of selegiline can be attributed to its 1-methamphetamine and amphetamine metabolites. These properties are absent in rasagiline and in its metabolite aminoindan. Parkinsonian patients receiving combined treatments with selegiline plus levodopa have been reported to have a higher mortality rate than those treated with levodopa alone (Lees, 1995). This is not related to its MAO-B inhibitory activity, but rather attributed to its sympathomimetic action and methamphetamine metabolites (Reynolds et al., 1978; Lavian et al., 1993).
Several propargylamine derivatives have been shown to selectively inhibit MAO-B and/or MAO-A activity and, thus to be suitable for treatment of neurodegenerative diseases such as Parkinson's and Alzheimer's disease. In addition, these compounds have been further shown to protect against neurodegeneration by preventing apoptosis.
R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof were first disclosed in U.S. Pat. Nos. 5,387,612, 5,453,446, 5,457,133, 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 as useful for the treatment of Parkinson's disease, memory disorders, dementia of the Alzheimer type, depression, and the hyperactive syndrome. The 4-fluoro-, 5-fluoro- and 6-fluoro-N-propargyl-1-aminoindan derivatives were disclosed in U.S. Pat. No. 5,486,541 for the same purposes.
U.S. Pat. Nos. 5,519,061, 5,532,415, 5,599,991, 5,744,500, 6,277,886, 6,316,504, 133, U.S. Pat. Nos. 5,576,353, 5,668,181, 5,786,390, 5,891,923, and 6,630,514 disclose R(+)-N-propargyl-1-aminoindan and pharmaceutically acceptable salts thereof as useful for treatment of additional indications, namely, an affective illness, a neurological hypoxia or anoxia, neurodegenerative diseases, a neurotoxic injury, stroke, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, and withdrawal symptoms.
U.S. Pat. No. 6,251,938 describes N-propargyl-phenylethylamine compounds, and U.S. Pat. Nos. 6,303,650, 6,462,222 and 6,538,025 describe N-propargyl-1-aminoindan and N-propargyl-1-aminotetralin compounds, said to be useful for treatment of depression, attention deficit disorder, attention deficit and hyperactivity disorder, Tourette's syndrome, Alzheimer's disease and other dementia such as senile dementia, dementia of the Parkinson's type, vascular dementia and Lewy body dementia.
The first compound found to selectively inhibit MAO-B was R-(−)-N-methyl-N-(prop-2-ynyl)-2-aminophenylpropane, also known as L-(−)-deprenyl, R-(−)-deprenyl, or selegiline. In addition to Parkinson's disease, other diseases and conditions for which selegiline is disclosed as being useful include: drug withdrawal (WO 92/21333, including withdrawal from psychostimulants, opiates, narcotics, and barbiturates); depression (U.S. Pat. No. 4,861,800); Alzheimer's disease and Parkinson's disease, particularly through the use of transdermal dosage forms, including ointments, creams and patches; macular degeneration (U.S. Pat. No. 5,242,950); age-dependent degeneracies, including renal function and cognitive function as evidenced by spatial learning ability (U.S. Pat. No. 5,151,449); pituitary-dependent Cushing's disease in humans and nonhumans (U.S. Pat. No. 5,192,808); immune system dysfunction in both humans (U.S. Pat. No. 5,387,615) and animals (U.S. Pat. No. 5,276,057); age-dependent weight loss in mammals (U.S. Pat. No. 5,225,446); schizophrenia (U.S. Pat. No. 5,151,419); and various neoplastic conditions including cancers, such as mammary and pituitary cancers. WO 92/17169 discloses the use of selegiline in the treatment of neuromuscular and neurodegenerative disease and in the treatment of CNS injury due to hypoxia, hypoglycemia, ischemic stroke or trauma. In addition, the biochemical effects of selegiline on neuronal cells have been extensively studied (e.g., see Tatton, et al., 1991 and 1993). U.S. Pat. No. 6,562,365 discloses the use of desmethylselegiline for selegiline-responsive diseases and conditions.
U.S. Pat. Nos. 5,169,868, 5,840,979 and 6,251,950 disclose aliphatic propargylamines as selective MAO-B inhibitors, neuroprotective and cellular rescue agents. The lead compound, (R)-N-(2-heptyl)methyl-propargylamine (R-2HMP), has been shown to be a potent MAO-B inhibitor and anti-apoptotic agent (Durden et al., 2000).
Propargylamine was reported many years ago to be a mechanism-based inhibitor of the copper-containing bovine plasma amine oxidase (BPAO), though the potency was modest. U.S. Pat. No. 6,395,780 discloses propargylamine as a weak glycine-cleavage system inhibitor. Copending U.S. patent application Ser. No. 10/952,379 discloses that propargylamine exhibits neuroprotective and anti-apoptotic activities and can, therefore, be used for all known uses of rasagiline and similar drugs containing the propargylamine moiety.
Copending U.S. patent application Ser. No. 10/952,367 of the present applicants discloses and claims a method for treatment of a cardiovascular disorder or disease which comprises administering to the subject an amount of an active agent selected from the group consisting of propargylamine, a propargylamine derivative, and a pharmaceutically acceptable salt thereof.
All and each of the above-mentioned US patents and patent applications are herewith incorporated by reference in their entirety as if fully disclosed herein.
To the best of our knowledge, the renal effects of rasagiline and its metabolites were not disclosed nor examined.